Abstract

Aim

We evaluated the efficacy of the PI3K inhibitor GDC-0941 (GDC) in combination with the angiogenesis inhibitor pazopanib (PAZ) in DDLPS xenografts with proven PI3K/AKT pathway activation.

Methods

NMRI nu/nu mice were either injected bilaterally with 5x106 SW872 cells or transplanted with human DDLPS (UZLX-STS3). Animals were randomized to 4 groups and treated for three weeks: vehicle, GDC (p.o., 75mg/kg/qd), PAZ (p.o., 40mg/kg/bid), GDC+PAZ (same dose/schedule as single agents). Efficacy was assessed by tumour volume, Western blotting of the signalling pathway and histological evaluation [mitosis, apoptosis, microvascular density (MVD)]. Statistics were performed using the Mann-Whitney U and Wilcoxon matched pairs tests. p<0.05 was defined as statistically significant.

Results

At the end of treatment, tumour shrinkage was observed in GDC and GDC+PAZ groups in SW872 bearing animals (38% and 52% decrease compared to baseline, p<0.05). In the patient-derived xenograft UZLX-STS3 GDC+PAZ delayed tumour growth as compared to either single agent (p<0.05). GDC as single agent caused a decrease in mitotic activity in both models (2.5 and 1.7 fold, respectively) and a 2.3 fold increase in apoptotic count in STS3 as compared to control (p<0.05). PAZ alone induced significantly lower mitotic counts in STS3 (1.8 fold), a 2.5 fold increase in apoptotic activity and significant inhibition of vascularisation as assessed by MVD (4.3 fold) compared to control group (p<0.05). In STS3 model the combination of GDC+PAZ caused an inhibition of proliferation (4.5 fold as compared to control, p<0.05), which was even more pronounced than for either single agent (p<0.05 for each), an increase in apoptosis (2.5 fold) and a decrease in vascularisation (3.3 fold) in comparison with untreated controls (p<0.05). In the both models, GDC alone suppressed the activation of the PI3K signalling pathway, which was more pronounced in GDC+PAZ treated tumours.

Conclusions

Combined inhibition of PI3K and angiogenesis results in enhanced antitumour efficacy in DDLPS mouse models which warrants further study in this highly aggressive disease.

Disclosure

P. Schöffski: Patrick Schöffski did receive honoraria for advisory and consulting functions and educational activities from Glaxo Smith Kline; L. Friedman: Lori Friedman is an employee of Genentech, a member of the Roche group. All other authors have declared no conflicts of interest.